Increased levels of circulating fatty acids can accumulate within liver hepatocytes and result in liver steatosis. The goal of this proposal is to advance the understanding of the molecular and cellular changes that underlie the genesis and pathogenesis of Nonalcoholic Fatty Liver Disease (NAFLD). We have performed DNA microarray analysis on normal aging mice and a mouse model of type 2 diabetes that exhibits liver steatosis. We identified CIDE-A (Cell death-inducing DNA fragmentation factor, alpha subunit-like effector A) as the most differentially expressed gene as a function of age. Increased expression of CIDE-A was also observed in the livers of type 2 diabetic mice exhibiting steatosis. Histology of liver tissue from old wild type mice and younger type 2 diabetic mice indicated that CIDE-A expression correlated with lipid accumulation in hepatocytes. We hypothesize that overexpression of CIDE-A in liver will cause steatosis (NAFLD). To test this hypothesis, transgenic mouse lines will be generated that constitutively express the CIDE-A cDNA in liver. Each transgenic line will be monitored at regular intervals throughout life for weight, biomarkers of liver function, glucose homeostasis, insulin resistance and changes in endocrine hormones. Additionally, liver from control mice and each transgenic line will be examined at various ages for lipid accumulation by NMR and microscopy. We will determine differences in organ weights (liver and fat depots), liver triacylglycerol content and rates of basal lipolysis. We will also determine the cellular localization of CIDE-A. Analysis of the data collected from this transgenic approach should support or refute the hypothesis that overexpression of CIDE-A in a transgenic mouse will result in liver steatosis. The elucidation of a role for CIDE-A in NAFLD may lead to the development of therapeutic agents that may improve liver pathologic status. PUBLIC HEALTH RELEVANCE: Obesity has become epidemic in most Western cultures. This increase has led to concomitant increases in obesity-related diseases such as non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes. We have identified a protein, CIDE-A, that we believe is a causative or contributing factor to the onset of NAFLD and have begun a program to further elucidate CIDE-A's function and identify inhibitors of this protein.